The invention is in the field of therapeutic organic compounds.
The recruitment of inflammatory cells into sites of inflammation is a normal physiological response designed to fight infection, remove damaged cells, and stimulate healing. However, the excessive recruitment of such cells often exacerbates tissue damage, slows healing, and in some cases leads to host death. Therefore, inhibition of inflammatory cell recruitment may be an appropriate therapeutic strategy in a number of inflammatory diseases, such as asthma, reperfusion injury, arthritis, and inflammatory bowel disease.
Chemokines constitute a diverse group of small secreted basic cytokine proteins that are shown to regulate the chemotactic migration and activation of a number of different leukocytes, particularly in the context of activation of the immune response during inflammatory conditions.
Examples of cells that have been shown to respond to chemokines, and in some cases become activated by chemokines, are neutrophils, eosinophils, basophils, monocytes, macrophages, B lymphocytes and different types of T lymphocytes, and stem cells as well as cancer cells.
Based on structural similarity, chemokines may be subdivided into four subfamilies, CXC, Cxe2x80x94C, C and CX3C, depending on the position of their first two cysteine residues. To date, at least 16 chemokine receptors, including nine CC-chemokine receptors and five CXC-chemokine receptors, have been identified and several more might be discovered
The chemokine known as RANTES (an abbreviation of the phrase xe2x80x9craised on activation, normal T-cell derived and secretedxe2x80x9d), has a sequence of 68 amino acid residues which identifies it as a beta-chemokine, a member of the Cxe2x80x94C chemokine subfamily which includes monocyte chemoattractants such as MIP-1 alpha, MIP-1 beta, MCP-1, MCP-2, and MCP-3. Although RANTES was originally identified in activated T lymphocytes, it has also been found to be inducible in a variety of cell types upon stimulation. Initial studies on RANTES-induced chemotaxis indicated that it elicits migratory responses of monocytes and memory T lymphocytes without showing any effect on neutrophiles. RANTES is reportedly a potent attractor for eosinophils, CD4+, CD45RO+ T-cells and basophiles. A receptor for RANTES has been cloned, which has been shown to bind chemokines in the order of affinity of MIP-1 alpha greater than RANTES. RANTES chemokine receptor CCR-3 was cloned from a human monocyte or an eosinophil library and subsequently shown to bind eotaxin, RANTES, and MCP-3.
A number of studies have suggested a role for RANTES in rheumatoid arthritis. Both RANTES mRNA and protein appear to be up-regulated in rheumatoid arthritis. Antibodies against RANTES significantly decreased the severity of ongoing clinical disease in a rat adjuvant-induced rheumatoid arthritis model.
It has been established that a number of chemokines including, KC, IP-10, MIP-1 alpha, RANTES, MARC (murine MCP-3), and TCA-3 (murine 1-309) are upregulated during the course of murine experimental allergic encephalitis (EAE), a mouse model of multiple sclerosis (MS). It has also been demonstrated that the chemokines JE (murine MCP-1), RANTES, MIP-1 alpha, IP-10, and KC are upregulated in the spinal cord and brain during the acute stages and chronic relapse of murine EAE. Co-localization studies demonstrated that in EAE MIP-1 alpha and RANTES, are produced exclusively by infiltrating leukocytes.
The principle chemokines that are elevated during acute rejection are thought to be those that interact with the receptors CCR-1 and CCR-5 (i.e., MIP-1 alpha, and RANTES) and recruit monocytes and T-cells. This suggests that antagonists that block these receptors might be beneficial for transplant rejection. Enhanced expression of various chemokines in rejected human allograft tissue has been documented, including RANTES. RANTES has also been shown to be elevated in the bronchoalveolar lavage of lung transplant recipients during rejection, especially in patients diagnosed with cytomegalovirus, a complication associated with accelerated rejection. It has also been reported that RANTES expression in cardiac allograft is linked to rejection in an experimental rat model. In humans, RANTES and MIP-1 alpha have been observed in the arteries of heart-transplant recipients undergoing accelerated atherosclerosis.
RANTES has been identified in asthmatic patients after allergen challenge.
Ligands for the CCR-1 receptor (MIP-1 alpha and RANTES) have been implicated in a number of chronic inflammatory diseases, including multiple sclerosis and rheumatoid arthritis. CCR-1 has also been found to play a significant role in allograft rejection. Chemokine receptors, CCR-1 and -5 and their natural ligands, MIP-1 alpha, and RANTES are thought to be involved in glomerular and interstitial lesions of human glomerular disease. CCR-1 is also found to be a major contributor to the airway remodeling responses that arise from Aspergillus fumigatus-induced allergic airway disease.
The inflammatory diseases known as acute gouty arthritis and acute pseudogout results from the deposition of monosodium urate monohydrate (MSUM) and Calcium pyrophosphate dihydrate (CPPD) [monoclinic (M) and triclinic (T)] crystals in the synovial joints of human. In the synovial fluid (SF) the crystals become coated with numerous proteins, including opsonizing species such as IgG and complement components. The interaction of protein coated crystals with neutrophils results in neutrophil respiratory burst activity, the generation of reactive oxygen species, degranulation and crystal phagocytosis (McCarty; Pathogenesis and treatment of crystal-induced inflammation.
RANTES, along with the natural ligands for the CCR-5 chemokine receptors, MIP-1 alpha, was found to inhibit human immuno-deficiency virus type-1 (HIV-1) infection, leading to the identification of CCR-5 as the major co-receptor for primary isolates of HIV-1, HIV-2 and SIV-1.
Neoabietic acid [8(14), 13(15)-abietadien-18-oic-acid], is a naturally-occurring tricyclic carboxylic acid of the following formula: 
Neoabietic acid (98(14), 13(15)-abietadien-18-oic-acid) is a naturally occurring resin acid found with other diterpene acids in rosin oils. Neoabietic acid is reportedly found in a variety of plants such as: Picea Schrenkiana, Pinus Palustris, Pinus Sylvastris, Pinus Siberica, Pinus massoniana and Pinus Panderosa. Neoabietic acid may be isolated from natural sources in a variety of ways, such as by solvent-solvent extraction, differential chromatographic techniques, column chromatography, gas chromatography and high-pressure liquid chromatography (Volkman, John K. et. al., (1993) J. Chromatogr. 643 (1-2) 209-219
Neoabietic acid has been suggested to have anti pesticidal uses (Kostka, et al., U.S. Pat. No. 6,039,966 issued Mar. 21, 2000).
In various aspects, the invention provides compounds that bind to one or more RANTES receptors for the treatment of chemokine mediated disease states. In some embodiments, the invention relates to the methods of using a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV) or (XV) or a pharmaceutically acceptable salt thereof, to formulate a medicament for the treatment of a chemokine mediated disease state, or to treat such a disease: 
(II) e.g., Kaurenolide [13013-56-4] (Hitchison, M. et. al., (1984) J. Chem. Soc., Perkin Trans I, 2363) 
(III) e.g., 7-Oxodehydro-abietic acid; or 7-Oxo-8,11,13-abietatrien-18-oic-acid 
(IV) e.g., alpha-Pimeric acid or [1R-(1 alpha, 4 beta, 4balpha, 7 alpha, 10a beta)]-7-Etheryl-1,2,3,4,4a,5,6,7,9,10,10a-dodecahydro-1,4a,7-trimethyl-1-phenanthrene carboxylic acid, isolated from American Rosin. 
(V) e.g., 1-Phenanthrenemethanamine-1,2,3,4,4a,9,10,10a-octahydro-1,4a-dimethyl-7-(1-methylethyl)-,[1R-(1 alpha,4a beta,10a alpha)]; or Dehydrabietylamine; or Rosin amine D [1446-61-3] (www.chemfinder.com) 
(VI) e.g., 12-Sulfo-dehydroabietic acid; or Ecabet (ref. Merck Index) 
(VII) e.g., Cassamine; or 7-[2-[2-(Dimethylamino)ethoxy]-2-oxoethylidene]tetradecahydro-1,4a,8-trimethyl-9-oxo-1-phenanthrenecarboxylic acid methyl ester; or Erythrophelamine (Merck Index) 
(VIII) e.g., Erythrophleine; or Norcassamidine; or [1S-(1 alpha, 4a alpha, 4b beta, 7E, 8 beta, 8a alpha, 9 alpha, 10a beta)]-Tetradecahydro-9-hydroxy-1,4a,8-trimethyl-7-[2-[2-(methylamino)ethoxy]-2-oxoethylidene]-1-phenanthrenecarboxylic acid methyl ester 
(IX) e.g., Dihydroabietic acid methyl ester [30968-45-7]
(X) e.g., Dehydroabietic acid [1740-19-8]
(XI) e.g., Cassaidine; or Dodecahydro-7 beta, 10-dihydroxy-1 alpha,-4b beta, 8,8-tetramethyl-2(1H)-phenanthrenylidene)acetic acid 2-(dimethylamino)ethyl ester (Merck Index) 
(XII) e.g., Cassaine; or Dodecahydro-7 beta -hydroxy-1 alpha,-4b beta, 8,8-tetramethyl-10-oxo-2(1H)-phenanthrenylidene)acetic acid 2-(dimethylamino)ethyl ester (Merck Index) 
(XIII) e.g., Neoabietic acid [471-77-2]
(XIV) Sandaraco-pimaric acid 
(XV) Ammonium Pimarate 
In the foregoing formulae, to the extent that substituents may be added to a given ring structure: xe2x80x9caxe2x80x9d may be 0 or an integer from 1 to 8; xe2x80x9cbxe2x80x9d may be 0 or an integer from 1 to 7; xe2x80x9ccxe2x80x9d may be 0 or an integer from 1 to 6; xe2x80x9cdxe2x80x9d may be 0 or an integer from 1 to 10; xe2x80x9cexe2x80x9d may be 0 or an integer from 1 to 10.
In alternative embodiments, rings A, B and C may be saturated or unsaturated, non-aromatic or aromatic, and may be substituted with one or more heteroatoms at different positions in the ring, such as oxygen, nitrogen or sulfur heteroatoms.
In alternative embodiments, R1, R2, R3 R4, R5 and R6 at each occurance may independently be selected from substituents having 50 or fewer atoms (such as fewer than 45, 40, 35, 30, 25, 20, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2) wherein the substituent may be selected from the group consisting of: H; substituted or unsubstitued alkyls, such as: C1-10 alkyls, C1-6 alkyls; substituted or unsubstitued cycloalkyls, such as C3-6 cycloalkyls; substituted or unsubstitued alkenyls, such as C2-6 alkenyls; substituted or unsubstitued alkynyls, such as C2-6 alkynyls; substituted or unsubstitued aryls; substituted or unsubstitued heterocycles; hydroxyls; aminos; nitros; thiols; primary, secondary or tertiary amines; imines; amides; phosphonates; phosphines; carbonyls; carboxyls; silyls; ethers; thioethers; sulfonyls; sulfonates; selenoethers; ketones; aldehydes; esters; xe2x80x94CF3; xe2x80x94CN; and combinations thereof, wherein the substituents may be linked to a ring, for example R4 and R5 substituents may be linked directly to Ring C (forming an additional ring as in Formula III) and R6 may be linked directly to Ring B. Accordingly, in alternative embodiments, an exocyclic ring structure may be present joining one or more of Rings A, B and C, such as an exocyclic ring involving position C3 and C10 or position C18 and C6 on Rings A and B. Similarly, an exocyclic ring structure between ring B and ring C may be formed involving C8 and C13. These exocyclic rings may be hetrocyclic, may be unsubstituted, or substitutes with one or more hetroatoms, such as nitro, amino, thio, hydro.
In alternative embodiments, compounds of the invention may be used as stereospecific isomers or mixtures thereof, selected on the basis of their chiral centres. There may be one or more chiral centers in the compounds of the invention and such compounds may therefore exist as various stereoisomeric forms. All such stereoisomers are included within the scope of the invention, unless a contrary indication is specifically set out herein. Some compounds may be prepared or isolated as racemates and may be used as such, individual enantiomers may also be isolated or preferentially synthesized by known techniques if desired. Such racemates and individual enantiomers and mixtures thereof are included within the scope of the present invention. Pure enantiomeric forms if produced may be isolated for example by preparative chiral HPLC.
In some embodiments, the chemokine may be RANTES and the chemokine receptor may be selected from the group consisting of CCR-1, CCR-3, CCR-4, and CCR-5.
In various embodiments, the invention provides for the use of compounds of the invention in the treatment of diseases selected from the group consisting of autoimmune diseases, acute inflammation, chronic inflammation, psoriasis, gout, acute pseudogout, acute gouty arthritis, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, cardiovascular, allograft rejection, such as renal allograft, cardiac allograft, kidney transplants, and other chronic transplant rejection, as well as glomerular and interstitial lesions of human glomerular disease, cancer, asthma, mononuclear-phagocyte dependent lung injury, reperfusion injury, idiopathic pulmonary fibrosis, sarcoidosis, focal ischemia, atopic dermatitis, chronic obstructive pulmonary disease, pulmonary fibrosis, adult respiratory distress syndrome, allergic airway disease, acute chest syndrome in sickle cell disease, inflammatory bowel disease, Crohn""s disease, ulcerative colitis, septic shock, endotoxic shock, urosepsis, glomerulonephritis, thrombosis, graft vs. host reaction, angiogenesis, atherosclerosis, multiple sclerosis and HIV-1 infections. In various aspects of the invention, alternative RANTES receptor ligands may be used to treat such diseases.
In one aspect, the invention provides methods for the use of neoabietic acid (which may be identified herein as CTCM189), as a chemokine-receptor-binding compound. In alternative embodiments, neoabietic acid may be a chemokine receptor ligand, such as a chemokine receptor agonist or a chemokine receptor antagonist. In some embodiments, neoabietic acid, or pharamaceutically acceptable salts thereof, may be used to treat chemokine or chemokine receptor mediated diseases. In some embodiments, the chemokine may be RANTES and the chemokine receptors may be selected from the group consisting of CCR-1, -3, -4, and -5.